2.1 Field of the Invention
The present invention relates to the field of boron-containing compounds, particularly compounds with antibacterial, anti-inflammatory, or both activities, and uses thereof. Methods for preparing and using these antibiotics, and pharmaceutical compositions thereof, are also provided.
2.2 The Related Art
Acne vulgaris is the most common skin disease which affects 85% of individuals at some time between the ages of 12- and 24 years. At present, 45 million people in the US have acne, while 17 million Americans seek treatment every year. Acne is a disease of the pilosebaceous unit, involving abnormalities in sebum production, follicular epithelial desquamation, bacterial proliferation and inflammation. The pathogenesis of acne is multifactorial, with microbial proliferation and inflammation acting as central mediators to this condition. In hair follicles, the mixture of cells and sebum creates an environment for the proliferation of Propionibacterium acnes (P. acnes), a bacterium that occurs commonly on the skin. Chemotactic factors released by P. acnes attract lymphocytes and neutrophils, as well as producing other pro-inflammatory molecules. This results in an inflammatory process where a plug composed of skin cells and sebum in sebaceous follicles is formed.
Current treatments for acne include antibiotics applied topically and systemically and also topical retinoids. However, these treatments are not satisfactory due to the long time course of therapy, which usually can take four to six weeks or longer. In addition, topical irritation and systemic side effects are also major issues with current products. Therefore, there is a need for an improved therapy for acne that is shorter acting, devoid of side effects, and inhibits both the bacterial and inflammatory contributors to the pathogenesis. The present invention addresses these problems by providing borinic esters that exhibit anti-inflammatory and/or antibacterial activities. Thus, the present invention represents a new modality for the treatment of acne.
Rosacea is a chronic skin disease that causes redness and swelling, mostly of the face and eyes. It is sometimes referred to as “adult acne”. The cause of rosacea is unknown and may be inherited. The disease affects 14 million Americans, occurs mostly in adults, is more common in women but is more severe in men. The current treatments are quite ineffective and may take weeks to months to see only a slight improvement. Thus, new therapies for rosacea are badly needed.
Acne and rosacea are common conditions that have a concomitant inflammatory component to their pathology. Inflammation is a defense reaction caused by tissue damage or injury, characterized by redness, heat, swelling, and pain. The primary objective of inflammation is to localize and eradicate the irritant and repair the surrounding tissue. For the survival of the host, inflammation is a necessary and beneficial process. The inflammatory response involves three major stages: first, dilation of capillaries to increase blood flow; second, microvascular structural changes and escape of plasma proteins from the bloodstream; and third, leukocyte transmigration through endothelium and accumulation at the site of injury. The leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site. These steps are not phases of inflammation, but represent the sequence of events from the perspective of each leukocyte. One goal of inflammation research is to develop methods to control inflammation by modulating or blocking leukocyte adhesion to the endothelium. This can result in the discovery of new anti-inflammatory agents. Anti-inflammatory agents function as blockers, suppressors, or modulators of the inflammatory response. The inflammatory response begins with a release of inflammatory chemicals into the extracellular fluid. Sources of these inflammatory mediators, the most important of which are histamine, prostaglandins, and cytokines, are injured tissue cells, lymphocytes, mast cells and blood proteins. The presence of these chemicals promotes and furthers the reactions to inflammation, which are redness, heat, swelling, and pain.
Anti-inflammatory drugs block or suppress the inflammatory response, preventing or reducing the appearance of adverse reactions to the irritant. Diseases and conditions such as acne, rosacea, asthma, arthritis, psoriasis and atopic dermatitis, for example, are treated with non-steroidal or steroidal anti-inflammatory agents. Aspirin and some other anti-inflammatory drugs exert their analgesic effects by inhibiting prostaglandin synthesis. In one aspect, the present invention relates to borinic esters that demonstrate anti-inflammatory activity by blocking the production of pro-inflammatory cytokines. These cytokines include, but are not limited to IL-1β, TNF-α, IL-6 and IL-8. The action of blocking these cytokines with compounds disclosed herein results in a reduction in the inflammatory components of redness, heat, swelling and pain.
While such treatments have historically required protracted therapeutic modalities, some drugs are not esthetically acceptable (often resulting in intense reddening, peeling, or drug coloration) which detract from patient adherence to the treatments. The products described herein are typically white colored and have enhanced stability. Thus, the present invention addresses a number of vexing diseases.